-
European Journal of Clinical... Nov 2023This systematic review and meta-analysis was conducted to synthesize the efficacy and safety of bempedoic acid in patients requiring lipid-lowering therapy. (Meta-Analysis)
Meta-Analysis Review
AIM
This systematic review and meta-analysis was conducted to synthesize the efficacy and safety of bempedoic acid in patients requiring lipid-lowering therapy.
METHODS
PubMed, Embase, and Scopus databases were searched for randomized controlled trials from inception till June 2023. The primary outcome was major adverse cardiovascular events (MACE), and secondary outcomes were all-cause mortality, serum lipid profile, and adverse events between bempedoic acid and comparators. ROB2 was used for risk of bias assessment. We pooled mean differences or relative risks (RR) along with 95% confidence intervals (random-effects model).
RESULTS
Five-hundred and thirty-one studies were screened and 17 (n = 21,131) were included for review. There was a significant reduction in the risk of MACE [RR, 0.88 (95% CI: 0.77 to 0.99), p = 0.03)] and all-cause mortality [RR, 0.90 (95% CI: 0.82 to 0.98), p = 0.02] following bempedoic acid treatment. Treatment with bempedoic acid led to a significant reduction in the mean serum total cholesterol [- 34.41 mg/dl (95% CI: - 42.43 to - 26.39), p < 0.001], low-density lipoprotein cholesterol (LDL-C) [- 33.91 mg/dl (95% CI: - 39.66 to - 28.17), p < 0.001], as well as high-density lipoprotein cholesterol (HDL-C) [- 2.40 mg/dl (95% CI: - 3.09 to - 1.71), p < 0.001] levels. However, there was a significant increase in the risk of hyperuricemia [RR, 2.05 (95% CI: 1.81 to 2.33), p < 0.001] following bempedoic acid treatment. The number needed to harm was large for all safety outcomes. The GRADE of evidence was moderate for all outcomes.
CONCLUSION
Bempedoic acid reduces the risk of MACE and all-cause mortality, lowers serum total cholesterol and LDL-C levels, and has a favorable safety profile. Trial registration ClinicalTrial.gov Identifier: CRD42023412837.
Topics: Humans; Cholesterol, LDL; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Randomized Controlled Trials as Topic; Dicarboxylic Acids; Fatty Acids
PubMed: 37672112
DOI: 10.1007/s00228-023-03555-8 -
Giornale Italiano Di Cardiologia (2006) Apr 2021Bempedoic acid (ETC-1002) is an oral, once-daily, small molecule with a half-life of 15-24 h. It is responsible for the inhibition of ATP citrate lyase (ACLY), a... (Review)
Review
Bempedoic acid (ETC-1002) is an oral, once-daily, small molecule with a half-life of 15-24 h. It is responsible for the inhibition of ATP citrate lyase (ACLY), a cytosolic enzyme upstream of HMG-CoA reductase. Bempedoic acid is a prodrug rapidly converted in the liver to a coenzyme A derivate, ETC-1200-CoA, by an endogenous liver very long-chain acyl-CoA synthetase-1 (ACSVL1). Since ACSVL1 is not present in the skeletal muscle, less risk of myalgia symptoms and myopathy is expected. In a Mendelian randomization study, combined exposure to variants in the ACLY, HMGCR and Niemann-Pick C1-Like 1 genes produced an additive decrease in low-density lipoprotein cholesterol levels and additive reduction in the risk of cardiovascular events. The aim of this review is to describe bempedoic acid mechanism of action, and its pharmacokinetic and pharmacodynamic characteristics.
Topics: ATP Citrate (pro-S)-Lyase; Dicarboxylic Acids; Fatty Acids; Humans; Liver
PubMed: 33847313
DOI: 10.1714/3582.35671 -
Clinical Therapeutics Feb 2021This article discusses the pharmacology of bempedoic acid, the trials that led to United States Food and Drug Administration (FDA) approval of its use, and the overall... (Review)
Review
PURPOSE
This article discusses the pharmacology of bempedoic acid, the trials that led to United States Food and Drug Administration (FDA) approval of its use, and the overall safety and efficacy of this therapy in heterozygous familial hypercholesterolemia, established atherosclerotic cardiovascular disease (ASCVD), and hyperlipidemia.
METHODS
A database search of PubMed and ClinicalTrials.gov was conducted for articles published between January 2012 to September 2020 and containing the key words bempedoic acid, ezetimibe, Nexletol and Nexlizet. Trials from the CLEAR series were selected, as they played a pivotal role in the establishment of FDA approval, along with additional trials published after FDA approval, which provided novel evidence on the use of bempedoic acid in the treatment of hypercholesterolemia. Publications that were not randomized, controlled trials were not included in this review. Only randomized controlled trials in which ezetimibe was used in conjunction with bempedoic acid were included in this review as they were relevant to the new FDA approval of bempedoic acid.
FINDINGS
The findings of the present review show that bempedoic acid is both an effective and well-tolerated option for the treatment of hypercholesterolemia when used without ezetimibe in addition to standard therapy. It also appears that the combination with ezetimibe increases the cholesterol-lowering effect more than either agent alone when added to standard therapy.
IMPLICATIONS
Hypercholesteremia continues to be a major contributing factor leading to ASCVD. Bempedoic acid is an additional treatment option, along with both statins and diet and exercise, for reducing cholesterol levels and ASCVD events. With the new FDA approval, bempedoic acid may offer an effective therapy for reducing low-density lipoprotein cholesterol in patients at high risk for cardiovascular events due to established ASCVD or heterozygous familial hypercholesterolemia.
Topics: Atherosclerosis; Dicarboxylic Acids; Drug Therapy, Combination; Ezetimibe; Fatty Acids; Humans; Hyperlipidemias; Hyperlipoproteinemia Type II; Hypolipidemic Agents
PubMed: 33384162
DOI: 10.1016/j.clinthera.2020.12.001 -
Atherosclerosis Nov 2023Sex-specific differences in the response to lipid-lowering therapies have been reported. Here, we assessed the effect of bempedoic acid in women and men using pooled,...
BACKGROUND AND AIMS
Sex-specific differences in the response to lipid-lowering therapies have been reported. Here, we assessed the effect of bempedoic acid in women and men using pooled, patient-level data from four phase 3 clinical trials of bempedoic acid.
METHODS
Patients were grouped into two pools: 1) atherosclerotic cardiovascular disease (ASCVD) and/or heterozygous familial hypercholesterolemia (HeFH) "on statins" and 2) "low-dose or no statin". Percent changes from baseline to at least week 12 in low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), total cholesterol (TC), apolipoprotein B (Apo B), and high-sensitivity C-reactive protein (hsCRP), as well as safety, were analyzed by statin pool and sex.
RESULTS
Overall, 3623 patients were included (bempedoic acid, 2425; placebo, 1198). Significant reductions in lipid parameters and hsCRP were observed with bempedoic acid vs. placebo in both sexes in the ASCVD and/or HeFH on statins (n = 3009) and the low-dose or no statin (n = 614) pools (p ≤ 0.002). Compared with men, women had significantly greater placebo-corrected reductions in LDL-C (-21.2% vs. -17.4%; p = 0.044), non-HDL-C (-17.3% vs. -12.1%; p = 0.003), TC (-13.8% vs. -10.5%; p = 0.012), and Apo B (-16.0% vs. -11.3%; p = 0.004) in the ASCVD and/or HeFH on statins pool. Women had similar reductions to men in lipid parameters in the low-dose or no statin pool and hsCRP in both pools. The safety of bempedoic acid was comparable between sexes.
CONCLUSIONS
In this pooled analysis, women experienced significant improvements in levels of LDL-C and other lipid parameters with bempedoic acid.
Topics: Male; Humans; Female; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Cholesterol, LDL; C-Reactive Protein; Hypercholesterolemia; Fatty Acids; Dicarboxylic Acids; Cholesterol; Atherosclerosis; Apolipoproteins B; Anticholesteremic Agents; Treatment Outcome
PubMed: 37648637
DOI: 10.1016/j.atherosclerosis.2023.117192 -
Advances in Applied Microbiology 2022Bio-based plastics production offers an alternative to the environmental problems posed by a significant reliance on fossil fuels. While dicarboxylic acids were...
Bio-based plastics production offers an alternative to the environmental problems posed by a significant reliance on fossil fuels. While dicarboxylic acids were essential bioplastic monomers, producing them on a large scale proved problematic. Recently, metabolic engineering has opened up interesting possibilities for producing dicarboxylic acids sustainably and efficiently. In this chapter, studies on the development of several dicarboxylic acid bioplastic monomers were presented. Furthermore, for different dicarboxylic acids, a variety of metabolic engineering strategies were highlighted, including improving the utilization rate of substrates, strengthening the catalytic efficiency of key enzymes, blocking branching pathways to balance metabolic flux, and improving cell physiological performance to promote biosynthesis. Finally, the remaining obstacles and solutions for building advanced dicarboxylic acid microbial systems were discussed.
Topics: Dicarboxylic Acids; Metabolic Engineering; Plastics
PubMed: 35933117
DOI: 10.1016/bs.aambs.2022.05.002 -
Atherosclerosis Aug 2023Bempedoic acid significantly lowers low-density lipoprotein cholesterol (LDL-C) in patients with hypercholesterolemia but its effects in patients with metabolic syndrome...
BACKGROUND AND AIMS
Bempedoic acid significantly lowers low-density lipoprotein cholesterol (LDL-C) in patients with hypercholesterolemia but its effects in patients with metabolic syndrome (MetS) have not been well characterized. We sought to determine the efficacy and safety of bempedoic acid in patients with hypercholesterolemia by baseline MetS status.
METHODS
This study used pooled data from four phase 3 studies. Using modified International Atherosclerosis Society guidelines, patients were grouped into two pools: those with and those without MetS. Patients with diabetes were excluded. Endpoints assessed change from baseline to week 12 in lipid and glycemic parameters and high-sensitivity C-reactive protein (hsCRP), and safety.
RESULTS
The study included 936 patients with MetS (bempedoic acid, 648; placebo, 288) and 1573 without MetS (bempedoic acid, 1037; placebo, 536). Significant placebo-corrected reductions in LDL-C were observed with bempedoic acid (p < 0.0001), with a slightly larger decrease in patients with vs. without MetS (-22.3% vs. -18.4%; interaction p = 0.0472). Compared with placebo, bempedoic acid significantly (p < 0.0001) lowered total cholesterol, non-high-density lipoprotein cholesterol, apolipoprotein B, and hsCRP, with a similar magnitude of benefit observed between MetS categories. Triglycerides increased with bempedoic acid but only to a lesser extent than with placebo in patients without MetS (placebo-corrected difference, -4.4%; p = 0.02). Only patients with MetS experienced decreases in glycated hemoglobin (-0.07%; p < 0.0001) and fasting plasma glucose (-2.4 mg/dL; p = 0.002). Safety was comparable between MetS categories and treatment groups.
CONCLUSIONS
These data suggest that bempedoic acid is a suitable therapy for patients with and without MetS who require additional lipid lowering.
Topics: Humans; Hypercholesterolemia; Cholesterol, LDL; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Metabolic Syndrome; C-Reactive Protein; Fatty Acids; Dicarboxylic Acids; Cholesterol; Treatment Outcome; Anticholesteremic Agents
PubMed: 37517922
DOI: 10.1016/j.atherosclerosis.2023.06.973 -
Metabolic Engineering Mar 2020Microbial production of chemicals and materials from renewable carbon sources is becoming increasingly important to help establish sustainable chemical industry. In this... (Review)
Review
Microbial production of chemicals and materials from renewable carbon sources is becoming increasingly important to help establish sustainable chemical industry. In this paper, we review current status of metabolic engineering for the bio-based production of linear and saturated dicarboxylic acids and diamines, important platform chemicals used in various industrial applications, especially as monomers for polymer synthesis. Strategies for the bio-based production of various dicarboxylic acids having different carbon numbers including malonic acid (C3), succinic acid (C4), glutaric acid (C5), adipic acid (C6), pimelic acid (C7), suberic acid (C8), azelaic acid (C9), sebacic acid (C10), undecanedioic acid (C11), dodecanedioic acid (C12), brassylic acid (C13), tetradecanedioic acid (C14), and pentadecanedioic acid (C15) are reviewed. Also, strategies for the bio-based production of diamines of different carbon numbers including 1,3-diaminopropane (C3), putrescine (1,4-diaminobutane; C4), cadaverine (1,5-diaminopentane; C5), 1,6-diaminohexane (C6), 1,8-diaminoctane (C8), 1,10-diaminodecane (C10), 1,12-diaminododecane (C12), and 1,14-diaminotetradecane (C14) are revisited. Finally, future challenges are discussed towards more efficient production and commercialization of bio-based dicarboxylic acids and diamines.
Topics: Diamines; Dicarboxylic Acids; Metabolic Engineering; Microorganisms, Genetically-Modified
PubMed: 30905694
DOI: 10.1016/j.ymben.2019.03.005 -
The New England Journal of Medicine Jun 2023
Topics: Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Dicarboxylic Acids; Fatty Acids
PubMed: 37379146
DOI: 10.1056/NEJMc2305917 -
The Annals of Pharmacotherapy Feb 2021To review the pharmacology, pharmacokinetics, safety, and efficacy of bempedoic acid for low-density lipoprotein cholesterol (LDL-C) reduction. (Review)
Review
OBJECTIVE
To review the pharmacology, pharmacokinetics, safety, and efficacy of bempedoic acid for low-density lipoprotein cholesterol (LDL-C) reduction.
DATA SOURCES
A PubMed search was conducted from January 2000 to June 15, 2020, using the keyword for phase III clinical trials published in the English language.
STUDY SELECTION AND DATA EXTRACTION
Articles related to the Food and Drug Administration (FDA) approval of bempedoic acid and other trials relating to the safety and efficacy of this drug were included.
DATA SYNTHESIS
The findings from this review show that bempedoic acid is a safe and effective option for lowering LDL-C levels in patients requiring LDL-C lowering for primary or secondary prevention of cardiovascular events.
RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE
Statin therapy remains the mainstay of treatment for both primary and secondary prevention. However, many patients cannot tolerate statin therapy because of statin-associated muscle symptoms. Bempedoic acid may be a reasonable adjunct for LDL-C reduction, though further evaluation of cardiovascular outcomes with bempedoic acid in this population is needed.
CONCLUSIONS
The recent FDA approval of bempedoic acid offers an additional option for lowering LDL-C levels in patients with atherosclerotic cardiovascular disease or heterozygous familial hyperlipidemia. Additional data regarding effect on long-term cardiovascular outcomes with bempedoic acid are currently being studied.
Topics: Atherosclerosis; Cholesterol, LDL; Clinical Trials, Phase III as Topic; Dicarboxylic Acids; Fatty Acids; Humans; Hypercholesterolemia; Hyperlipoproteinemia Type II; Hypolipidemic Agents; Treatment Outcome
PubMed: 32674598
DOI: 10.1177/1060028020941083 -
Deutsche Medizinische Wochenschrift... Jan 2021Atherosclerotic cardiovascular disease (ASCVD) remains a leading cause of morbidity and mortality. The fact that elevated levels of low-density lipoprotein-cholesterol...
Atherosclerotic cardiovascular disease (ASCVD) remains a leading cause of morbidity and mortality. The fact that elevated levels of low-density lipoprotein-cholesterol (LDL-C) play a causal role in the development of ASCVD is now well accepted, given the results of numerous epidemiological and genetic studies, as well as randomized controlled clinical trials. Statins have become a primary therapeutic cornerstone in ASCVD prevention since they have been shown to reduce CV events by reducing levels of LDL-C. But despite the proven efficacy and safety of statin therapy, several aspects indicate a substantial need for additional or alternative LDL-C lowering therapies. These aspects include not only a high variability in individual response to therapy, but also possible side effects, potentially reducing adherence to treatment. Most importantly, an elevated risk for cardiovascular (CV) events remains in a large proportion of high-risk patients, especially in those with persistent elevation of LDL-C levels despite a maximum tolerated dose of statin therapy. Also, large clinical trials currently investigate a potential CV benefit of drug therapies targeting elevated levels of triglycerides and lipoprotein (a), respectively.
Topics: Atherosclerosis; Cholesterol, LDL; Dicarboxylic Acids; Fatty Acids; Fatty Acids, Omega-3; Humans; Hypolipidemic Agents; Oligonucleotides, Antisense; RNA, Small Interfering
PubMed: 33465805
DOI: 10.1055/a-1199-8496